期刊
EMBO JOURNAL
卷 39, 期 13, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020104926
关键词
actin-based motility; gram-negative; guanylate binding proteins; lipopolysaccharide; O-antigen
资金
- National Institutes of Health [AI139425, AI28360, AI081724]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [427472513, HE2679/6-1]
- Harvard Medical School Dean's Innovation Award
- Burroughs Wellcome Fund
- National Science Foundation as part of the National Nanotechnology Coordinated Infrastructure (NNCI) [ECCS-1542015]
In the outer membrane of gram-negative bacteria, O-antigen segments of lipopolysaccharide (LPS) form a chemomechanical barrier, whereas lipid A moieties anchor LPS molecules. Upon infection, human guanylate binding protein-1 (hGBP1) colocalizes with intracellular gram-negative bacterial pathogens, facilitates bacterial killing, promotes activation of the lipid A sensor caspase-4, and blocks actin-driven dissemination of the enteric pathogen Shigella. The underlying molecular mechanism for hGBP1's diverse antimicrobial functions is unknown. Here, we demonstrate that hGBP1 binds directly to LPS and induces detergent-like LPS clustering through protein polymerization. Binding of polymerizing hGBP1 to the bacterial surface disrupts the O-antigen barrier, thereby unmasking lipid A, eliciting caspase-4 recruitment, enhancing antibacterial activity of polymyxin B, and blocking the function of the Shigella outer membrane actin motility factor IcsA. These findings characterize hGBP1 as an LPS-binding surfactant that destabilizes the rigidity of the outer membrane to exert pleiotropic effects on the functionality of gram-negative bacterial cell envelopes.
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